DIRECT EFFECTS OF EMPAGLIFLOZIN ON EXTRACELLULAR MATRIX REMODELING IN HUMAN CARDIAC FIBROBLASTS: NOVEL TRANSLATIONAL CLUES TO EMPA-REG OUTCOME

Abstract BACKGROUND Empagliflozin, an SGLT2 inhibitor, has shown remarkable reductions in cardiovascular mortality and heart failure admissions (EMPA-REG OUTCOME). However, the mechanism underlying the heart failure protective effects of empagliflozin remains largely unknown. Cardiac fibroblasts play an integral role in the progression of structural cardiac remodeling and heart failure, in part, by regulating extracellular matrix (ECM) homeostasis. Thus, the objective of this study was to determine if empagliflozin has a direct effect on human cardiac myofibroblast-mediated ECM remodeling. METHODS Cardiac fibroblasts were isolated via explant culture from human atrial tissue obtained at open-heart surgery. Collagen gel contraction assay was used to assess myofibroblast activity. Cell morphology and cell-mediated ECM remodeling was examined using confocal microscopy. Gene expression of pro-fibrotic markers was assessed using RT-qPCR. RESULTS Empagliflozin significantly attenuated TGFβ1-induced fibroblast activation via collagen gel contraction after 72-hour exposure with escalating concentrations (0.5μM, 1μM, and 5μM) resulting in greater attenuation. Morphological assessment showed myofibroblasts exposed to empagliflozin were smaller in size with shorter and fewer number of extensions, indicative of a more quiescent phenotype. Moreover, empagliflozin significantly attenuated cell-mediated ECM remodeling as measured by collagen fiber alignment index. Gene expression profiling revealed significant suppression of critical pro-fibrotic markers by empagliflozin including: COL1A1, ACTA2, CTGF, FN1, and MMP-2. CONCLUSIONS We provide novel data showing a direct effect of empagliflozin on human cardiac myofibroblast phenotype and function by attenuation of myofibroblast activity and cell-mediated collagen remodeling. These data provide critical insights into the profound effects of empagliflozin as noted in the EMPA-REG OUTCOME study.